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Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies

  • Published on June 28, 2018
  • Drug Drug Interactions (DDI)
  • Publications

Jane R Kenny, Diane Ramsden, David B Buckley, Shannon Dallas, Conrad Fung, Michael Mohutsky, Heidi J Einolf, Liangfu Chen, Joshua G Dekeyser, Maria Fitzgerald, Theunis C Goosen, Y Amy Siu, Robert L Walsky, George Zhang, Donald Tweedie and Niresh Hariparsad
Drug Metabolism and Disposition June 29, 2018, dmd.118.081927; DOI: https://doi.org/10.1124/dmd.118.081927

Abstract

The IQ induction working group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC50 data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary. A large degree of variability was observed in both the clinical and in vitro induction responses, yet analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large dataset, the following recommendations are proposed. (a) CYP induction should continue to be evaluated in three separateHuman donors in vitro. (b) In light of empirically divergent responses in rifampicin control and most test inducers, normalization of data to percent positive control appears to be of limited benefit. (c) Two-fold induction, with concentration dependence, is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction. (d) To reduce the risk of false positives, in the absence of a concentration dependent response, induction o ≥ 2-fold should be observed in more than one donor to classify a compound as an in vitro inducer. (e) If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be o ≥10-fold. (f) Inclusion of a negative control adds no value beyond that of the vehicle control…

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